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Kang, Dong Woo,Lee, Shin Wha,Hwang, Won Chan,Lee, Bo Hui,Choi, Yong-Seok,Suh, Young-Ah,Choi, Kang-Yell,Min, Do Sik American Association for Cancer Research 2017 Cancer Research Vol.77 No.1
<P>A phospholipase that functions as a nodal modifier of colon cancer susceptibility mediates the cross-talk between two major tumor suppressor and oncogenic pathways, with implications for disease-selective therapeutic targeting.</P><P>The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the <I>Apc<SUP>min/+</SUP></I> mouse model of intestinal tumorigenesis. Mechanistic investigations revealed that genetic and pharmacologic targeting of PLD1 promote the E2F1-dependent apoptotic program via both miR-192/4465–mediated downregulation of RB1 and inhibition of Akt–TopBP1 pathways. Moreover, the miRNA–RB1 axis and Akt pathway also contributed to the PLD1-mediated self-renewal capacity of colon cancer–initiating cells. Finally, PLD1-driven E2F1 target gene expression positively correlated with tumor stage in patients with colorectal cancer. Overall, our findings suggest that PLD1 mediates cross-talk between multiple major signaling pathways to promote the survival and malignancy of colon cancer cells and may therefore represent an ideal signaling node for therapeutic targeting. <I>Cancer Res; 77(1); 142–52. ©2016 AACR</I>.</P>
Kang, Dong Woo,Yang, Eun Sun,Noh, Yu Na,Hwang, Won Chan,Jo, Se‐,Young,Suh, Young‐,Ah,Park, Won Sang,Choi, Kang‐,Yell,Min, Do Sik John Wiley Sons, Ltd 2017 The Journal of pathology Vol.241 No.5
<P><B>Abstract</B></P><P>Infection with <I>Helicobacter pylori</I> is closely linked to an increased risk of gastric cancer. Although cytotoxin‐associated gene A (CagA), a major virulence factor of <I>H. pylori</I>, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer‐initiating cell (CIC)‐like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of β‐catenin and its target CIC markers via downregulation of microRNA (miR)‐320a and miR‐4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR‐320a and miR‐4496 attenuated the <I>in vitro</I> self‐renewal and tumour‐initiating capacity of CagA‐expressing CICs by targeting β‐catenin. Moreover, miR‐320a and miR‐4496 decreased CagA‐induced chemoresistance by targeting ATP‐binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post‐transcriptional levels, respectively. Combination therapy with 5‐fluorouracil and miR‐320a/miR‐4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA‐induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with <I>H. pylori</I> are linked to CagA‐induced upregulation of β‐catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA‐induced carcinogenisis and the therapeutic potential of of miR‐320a and miR‐4496. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</P>
Kang, Dong Woo,Lee, Bo Hui,Suh, Young-Ah,Choi, Yong-Seok,Jang, Se Jin,Kim, Yong Man,Choi, Kang-Yell,Min, Do Sik American Association for Cancer Research 2017 Clinical Cancer research Vol.23 No.23
<P><B>Purpose:</B> Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling.</P><P><B>Experimental Design:</B> Expression of ICAT via targeting of PLD1 was assessed <I>in vivo</I> in <I>Apc<SUP>Min/</SUP></I><SUP>+</SUP> mice, an AOM/DSS model, and <I>in vitro</I> using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying <I>APC</I> and <I>PI3K</I> mutations.</P><P><B>Results:</B> PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways.</P><P><B>Conclusions:</B> These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying <I>APC</I> and <I>PI3KCA</I> mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. <I>Clin Cancer Res; 23(23); 7340–50. ©2017 AACR</I>.</P>
Functional Regulation of Phospholipase D Expression in Cancer and Inflammation
Kang, Dong Woo,Choi, Kang-Yell,Min, Do Sik American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.33
<P>Phospholipase D (PLD) regulates downstream effectors by generating phosphatidic acid. Growing links of dysregulation of PLD to human disease have spurred interest in therapeutics that target its function. Aberrant PLD expression has been identified in multiple facets of complex pathological states, including cancer and inflammatory diseases. Thus, it is important to understand how the signaling network of PLD expression is regulated and contributes to progression of these diseases. Interestingly, small molecule PLD inhibitors can suppress PLD expression as well as enzymatic activity of PLD and have been shown to be effective in pathological mice models, suggesting the potential for use of PLD inhibitors as therapeutics against cancer and inflammation. Here, we summarize recent scientific developments regarding the regulation of PLD expression and its role in cancer and inflammatory processes.</P>
Kang, Dong Woo,Choi, Chi Yeol,Cho, Yong-Hee,Tian, Huasong,Di Paolo, Gilbert,Choi, Kang-Yell,Min, Do Sik The Rockefeller University Press 2015 The Journal of experimental medicine Vol.212 No.8
<▼1><P>Kang et al. show that genetic or pharmacological inactivation of the enzyme phospholipase D1 (PLD1) disrupts colitis-associated intestinal tumorigenesis by suppressing the self-renewal capacity of colon cancer stem cells.</P></▼1><▼2><P>Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in <I>Apc<SUP>Min/+</SUP></I> and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell–specific PLD1 overexpression in <I>Apc<SUP>Min/+</SUP></I> mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with <I>Apc<SUP>Min/+</SUP></I> mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer–initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1–miR-4496–β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis.</P></▼2>